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Synthesis of Steroidal Modulators for Bile Acid Receptors
Kašpar, Miroslav ; Kudová, Eva (advisor) ; Drašar, Pavel (referee) ; Kvasnica, Miroslav (referee)
The Thesis comprises three major projects. The first project is concerned with the creation of a pregnane compound library that can be used to explore the structure-activity relationship with the TGR5 and FXR receptors. The project draws structural inspiration from Sato's work and involves the compound characterization, digitization, computational methods, and biochemical analysis of a historic group collection of steroids. The second project focuses on the synthesis of modified bile acids using Grignard, Wittig, cross-coupling, or cycloaddition reactions. The synthesized compounds were tested for their TGR5 and FXR activity, leading to the discovery of (E)-7-ethylidene-3α-hydroxy-5β- cholan-24-oic acid, which is known to be the only bile acid with TGR5/FXR dual action. In the last part of the Thesis, 16 oxidizing agents were tested on 5 substrates for their selectivity in oxidizing axial or equatorial hydroxyl groups.
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